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Urology Research Laboratory
Harrison Department of Surgical Research
Dr. Samuel K. Chacko
 
Research Personnel
 
Samuel K. Chacko, D.V.M., Ph.D.

Current Projects
Professor of Pathology, School of Veterinary Medicine
Director, Basic Urological Research
Division of Urology, Department of Surgery
University of Pennsylvania School of Medicine
500 South Ridgeway Avenue
Glenolden, PA 19036
Phone: 267-350-9601
Fax: 267-350-9610
Email: chackosk@mail.med.upenn.edu
 
Education/Training
1963 B.V.Sc. (U.S Equivalent, D.V.M.)
Kerala Veterinary College & Research Institute
University of Kerala, India
   
1969 Ph.D. in Experimental Pathology
University of Pennsylvania
Philadelphia, Pennsylvania
 
Research Interest

Pathobiology of smooth muscle, signal transduction, myosin, thin filament-associated protein caldesmon, smooth muscle cell differentiation, and translational research.

Female Urology: Our laboratory is interested in the pathogenetic mechanisms for pelvic floor prolapse, particularly in the role of vaginal smooth muscle tone on vaginal prolapse in menopausal women. We are also investigating the role of estrogen in a) the remodeling of the detrusor smooth muscle during bladder outlet obstruction, b) maintaining the urethral tone and c) bladder overactivity seen in older women.

 
Research Description

The major research focus in Dr. Chacko’s laboratory are:

Molecular/Cellular Mechanisms For Smooth Muscle Contractile Dysfunctions:
Our experiments to study the mechanisms for contractile dysfunctions are directed to understand the regulation of actomyosin ATPase and contraction in normal and pathological smooth muscles. Specifically, the roles of smooth muscle myosin isoforms, myosin light chain phosphorylation, and thin filament-associated proteins (caldesmon and calponin) in actin-myosin interaction and cross-bridge cycling are investigated.

Remodeling Of Urinary Bladder Smooth Muscle In Outlet Obstruction:
Molecular mechanisms for the regulation of actin-myosin interaction and contraction in normal and hypertrophied smooth muscle. A rabbit model for outlet obstruction is used to elucidate the mechanisms for altered contractility of the detrusor smooth muscle in men with outlet-obstruction in benign prostatic hyperplasia. This study is part of the George O'Brien Urology Research Center supported by a Center Grant from the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK), National Institute of Health (NIH).

Molecular Mechanisms For Erectile Function And Dysfunction In Men:
Cell and molecular biology of the contractile function of smooth muscle cells in the corpus cavernosum penis from normal rabbits and men with erectile dysfunctions. The present research focuses on the signal transduction pathway that is responsible for the GTP-mediated relaxation of the smooth muscle in the penis. In addition, we investigate the role of free radicals on the contractility of corpus cavernosum smooth muscle in alloxan-induced diabetes in rabbits.

Mechanisms For The Urinary Bladder Dysfunction In Diabetes:
Molecular and biochemical mechanisms for the altered contractility of the detrusor smooth muscle in diabetes are studied using streptozotocin-induced and alloxan-induced diabetes in rats and rabbits, respectively. The investigation includes the expression of isoforms of proteins (PK-C, MLCK, Rho-kinase, myosin, etc) involved contractile proteins and proteins involved in signal transduction.

Cytodifferentiation Of Smooth Muscle:
Differentiation of smooth muscle phenotypes during development. Transcriptional regulation of myosin isoforms in developing and pathological smooth muscle in the bladder wall is investigated.

Technical Approaches include expression of contractile proteins using a bacculovirus expression system, site directed mutagenesis, gene knockouts, in situ hybridization, immunohistochemistry, in vitro motility assay & enzymatic assays to study the actin-myosin interaction, and studies using fluorescent labeled proteins to study protein conformation during protein-protein interaction.

 
Selected Publications
  1. Chacko, S. (1973) DNA synthesis, mitosis, and differentiation in cardiac myogenesis. Dev. Biol. 35:272774-84.
  2. Blose, S.H., Shelanski, M.L. and Chacko, S. (1976) Localization of bovine neurofilament antibody to intermediate filaments in endothelial cells. J. Cell. Biol., 70:459-466.
  3. Chacko S., Conti, MA, and Adelstein, RS. (1977). The effect of phosphorylation of smooth muscle myosin on actin activation and Ca2+ regulation. Proc. Natl. Acad. Sci. (USA). 74:129-133.
  4. Chacko, S. (1981) Effect of phosphorylation Ca2+ and tropomyosin on actin-activated ATPase activity of mammalian smooth muscle myosin. Biochemistry. 20:702-703.
  5. Chacko, S. and Rosenfeld, A. (1982) Regulation of actin-activated hydrolysis by arterial myosin. Proc. Natl. Acad. Sci. (USA) 79:292-296.
  6. Miyata, H. and Chacko, S. (1986) Role of tropomyosin in smooth muscle contraction: The effect of tropomyosin binding to actin on actin-activation of myosin ATPase. Biochemistry. 25:2725-2729.
  7. Horiuchi, KY., and Chacko, S. (1989) Caldesmon Inhibits the cooperative turning-on of the smooth muscle heavy meromyosin by tropomyosin-actin. Biochemistry,28:9111-911.
  8. Chacko, S. and Eisenberg, E. (1990). Cooperativity of gizzard acto-HMM ATPase in the presence of gizzard tropomyosin. J. Biol.Chem.265:2105-2110.
  9. Samuel, M., Chowrashi, PK., Pepe, FA., and Chacko, S. (1990) Effects of phosphorylation, magnesium, and filament assembly on actin-activated ATPase of pig urinary bladder myosin. Biochemistry 29:7124-3132.
  10. Horiuchi, KY., Samuel, M., and Chacko, S. (1991) Mechanism for inhibition of acto-HMM ATPase by the actin/calmodulin binding domain of caldesmon. Biochemistry 30:712-717.
  11. Horiuchi, KY., and Chacko, S. (1991) The mechanism for the inhibition of actin-activated ATPase of smooth heavy meromyosin by calponin. Biochem. Biophys. Res. Commun. 176:1487-1493.
  12. Chacko, S., Jacob, S., Horiuchi, K. (1994) Myosin I from mammalian smooth muscle is regulated by caldesmon-calmodulin. J. Biol. Chem. 269:1583-15807.
  13. Wang, Z., Horiuchi, KY., Jacob, SJ., Gopalakurup, SK, and Chacko, S. (1994) Overexpression, purification, and characterization of full-length and mutant caldesmon using a baculovirus expression system. J. Musc. Res. & Cell Motil. 15: 646-658.
  14. Horiuchi, KY. and Chacko, S. (1995) Effect of unphosphorylated smooth muscle on caldesmon-mediated regulation of actin filament velocity. J. Musc. Res. & Cell Motil. 16:11-19.
  15. Horiuchi, KY., Wang, Z., and Chacko, S. (1995) Inhibition of smooth muscle actomyosin ATPase by caldesmon is associated with caldesmon-induced conformational changes in tropomyosin bound to actin. Biochemistry.34: 16815.
  16. Wang, Z. , Horiuchi, KY., and Chacko, S. (1996) Characterization of the functional domains of the C-terminal region of caldesmon using full-length and mutant caldesmon molecules. J. Biol. Chem. 271:271:2234-2242.
  17. Wang, Z. and Chacko, S. (1996) Mutagenesis analysis of functionally important domains within the C-terminal end of smooth muscle caldesmon. J. Biol. Chem. 27:25707-25714.
  18. DiSanto, ME., Cox, RH., Wang, Z., and Chacko, S. (1997) Increased expression of myosin II with insertion in the NH2-terminal region of the distributing (muscular) arteries. Amer. J.Physiol. 272(Cell) C1532-C1542.
  19. Wang, Z., Yang, Z-Q., and Chacko, S. (1997) Functional and structural relationship between the calmodulin-binding, actin-binding, and actomyosin-ATPase inhibitory domains on the C terminus of smooth muscle caldesmon .J. Biol. Chem.272: 16896-16903.
  20. Chacko, S., DiSanto, M., Wang, Z, Zderic, SA., and Wein, AJ. (1997).Contractile protein changes in urinary bladder smooth muscle during obstruction-induced hypertrophy. Scand. J.Urol. Neprol. 184: 67-76.
  21. Wang, Z., He, J., Yang, Z-Q., and Chacko, S. (1997) Both N-terminal myosin binding and C-terminal actin-binding sites on smooth muscle caldesmon are required for caldesmon-mediated inhibition of actin filament velocity. Proc. Natl Acad. Sci. 94: 11899-11904.
  22. Menon, C., and Chacko, S. (1998) Expression of caldesmon during differentiation of smooth muscle in the chicken gizzard. Tissue & Cell Res. 30:118-126
  23. DiSanto, M., Chacko, T., Hypolite, J., Broderick, G., Wein, AJ, and Chacko, S. (1998) Molecular Basis of Erecetile Function: Expression of myosin isoforms in smooth muscle cells in corpus cavernosum penis. Am. J. Physiology (Cell Physiol 44) 275:C976-C987.
  24. Gomes, CM., DiSanto, ME., Horan, P., Levine, RM., Wein, AJ., and Chacko, S. (2000) Improved contractility obstructed bladders after tadenan treatment is associated with reversal of altered myosin isoform expression. J. Urol. 163: 2008-2013.
  25. Hypolite, J., DiSanto, M., Zheng, Y., Chang, S., Wein, A., and Chacko, S. (2001) Regional variation on myosin isoforms and phosphorylation at the resting tone in urinary bladder smooth muscle. Am. J. Physiol.(Cell) 280: C254-C264
  26. Sanchez-Ortiz, R., Wang, Z., Menon, C., DiSanto, ME., Wein, AJ, and Chacko, S. (2001). Estrogen modulates the expression of myosin heavy chain in detrusor smooth muscle. Am. J. Physiol. (Cell) 280: C433-C440.
  27. Arafat, HA., Kim, G., DiSanto, ME., Wein, AJ, and Chacko, S. (2001) Heterogeneity of bladder myocytes in vitro: modulation of myosin isoform expression. Tissue & Cell. 33 (3) 1-14.
  28. Chang, S., Hypolite, J., Zderic, SA., Wein, AJ., Chacko, S., DiSanto, ME (2002) Enhanced force generation by corpus cavernosum smooth muscle in rabbits with partial bladder outlet obstruction. J. Urol 167:2636-2644.
  29. Zheng, Y., Weber, W.T., Wang, S., Wein, A.J., Chacko, S., and DiSanto, M.E. (2002) Establishment of a phenotypically stable bladder myocyte cell line from hypertrophied detrusor smooth muscle. Am. J. Physiol Cell Physiology 283:C373-382.
  30. Chang, S., Hypolite, J., Changolkar, A., Wein, AJ., Chacko, S., DiSanto, ME (2003) Increased contractility of diabetic rabbit copora smooth muscle in response to endothelin is mediated via Rho-kinase ß. Int J Impot Res 15: 53-62.
  31. DiSanto ME, Stein R, Chang S, Hypolite JA, Zheng Y, Zderic S, Wein AJ, Chacko S. (2003) Alteration in the expression of myosin isoforms in detrusor smooth muscle following bladder outlet obstruction. Am J Physiol Cell Physiol., 285(6):C1397-410.
  32. Bing W, Chang S, Hypolite JA, DiSanto ME, Zderic SA, Rolf L, Wein AJ, Chacko S. (2003) Obstruction-induced changes in urinary bladder smooth muscle contractility: A role for Rho-kinase. Am J Physiol Renal Physiol. ;285(5):F990-7.
  33. Zhang E, Stein R, Chang S, Zheng Y, Zderic SA, Wein AJ, and Chacko S. (2004) Smooth Muscle Hypertrophy following Partial Bladder Outlet Obstruction is Associated with Overexpression of Non-Muscle Caldesmon. Am J. Pathology.,164: 601-612.
  34. Austin JC; Chacko SK; DiSanto M; Canning DA; Zderic SA; (2004) A male murine model of partial bladder outlet obstruction reveals changes in detrusor morphology, contractility and Myosin isoform expression Journal of Urology 172(0): 1524-1528.
  35. Su X; Changolkar A; Chacko S; Moreland RS; (2004) Diabetes decreases rabbit bladder smooth muscle contraction while increasing levels of myosin light chain phosphorylation Am J Physiol Renal Physiol 287(4): F690-9.
  36. Chang S; Hypolite JA; Velez M; Changolkar A; Wein AJ; Chacko S; DiSanto ME; (2004) Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits Am J Physiol Regul Integr Comp Physiol 287(4): R950-60.
  37. Chacko S.; Chang S;Hypolite J;DiSanto ME;Wein AJ; (2004) Alteration of Contractile and Regulatory Proteins Following Partial Bladder Outlet Obstruction. Scandinavian Journal of Urology & Nephrology, 215:26-36.
  38. Chang S, Hypolite JA, Wein AJ, Chacko S, Disanto ME (2005) Increased corpus cavernosum smooth muscle tone associated with partial bladder outlet obstruction is mediated via Rho-kinase. Am J Physiol Regul Integr Comp Physiol.;289(4):R1124-30.
  39. Changolkar A; Hypolite J; DiSanto ME; Oates P; Wein AJ; Chacko S; (2005) Diabetes-Induced Decrease in Detrusor Smooth Muscle Force is Associated with Oxidative Stress and Overactivity of Aldose Reductase. Journal of Urology 173:309-313.
  40. Mannukarottu, AS., Hypolite, JA., Zderic. SA., Wein, AJ., Chacko, S., DiSanto, ME. (2005) Regional Alterations in the Expression of Smooth Muscle Myosin Isoforms in Response to Partial Bladder Outlet Obstruction. Journal of Urology 173:302-308.
  41. Chang S, Hypolite JA, Disanto ME, Changolkar A, Wein AJ, Chacko S (2005) Increased basal phosphorylation of detrusor smooth muscle myosin in Alloxan-induced diabetic rabbit is mediated by up-regulation of Rho-kinase {beta} and CPI-17. Am J Physiol Renal Physiol. 290(3):F650-6.
  42. Mannukarottu, AS., DiSanto, ME., Zderic. SA., Wein, AJ., Chacko, S (2005) Altered expression of thin filament-associated proteins in hypertrophied urinary bladder smooth muscle. Neurourol Urodyn. 25(1):78-88.
  43. Mannukarottu, AS., DiSanto, ME., Zderic, SA., Wein, AJ., Chacko, S (2006)Altered expression of thin filament-associated proteins in hypertrophied urinary bladder smooth muscle. Neurourol Urodyn. 25(1):78-88.
  44. Hypolite JA, Chang S, Zheng Y, DiSanto ME, Zderic SA, Wein AJ, Chacko S (2006) Partial bladder outlet obstruction induces urethral smooth muscle hypertrophy and decreased force generation. J Urol. 175(2):777-82.
  45. Macarak, EJ., Schultz, J., Zderic, SA., Sado, Y., Polyak, E., Chacko, S, and Howard, PS. (2006) Smooth muscle trans-membrane sarcoglycan complex in partial bleadder ouitlet obstruction. Histochemistry. Cell Biol. 2006 Jan 25;1-12.
  46. LaBelle E., Zderic, SA., Delaney, D., Hypolyte, J., Wein, A.J. and Chacko, S. (2006)Lipid signaling changes in smooth muscle remodeling associated with partial urinary bladder outlet obstruction. Neurourol Urodyn.;25(2):179-84.
  47. Basha, M., Chang, S., Somolock, E.M., Moreland, R.S., Wein, A.J., and Chacko S. (2006) Regional differences in myosin heavy chain isoform expression and maximal shortening velocity of rat vaginal wall smooth muscle. Am. J. Physiol. Regul Integr. Comp. Physiol 291(4):R1076-84.
  48. Stanton MC, Austin JC, Delaney DP, Gosfield A, Marx JO, Zderic SA, Chacko S, Moreland RS. (2006) Partial bladder outlet obstruction selectively abolishes protein kinase C induced contraction of rabbit detrusor smooth muscle. J Urol, 176(6 Pt 1):2716-21.
  49. Deng M, Mohanan S, Polyak E, Chacko S.(2007) Caldesmon is necessary for maintaining the actin and intermediate filaments in cultured bladder smooth muscle cells. Cell Motil Cytoskeleton, 64(12):951-65.
  50. Hypolite JA, Chang S, LaBelle, E, Babu, G., Periasamy M, Wein AJ, and Chacko S (2008) Deletion of SM-B, the high ATPase isoform of myosin, upregulates the PKC-mediated signal transduction pathway in murine urinary bladder smooth muscle. Am J Physiol Renal Physiol. 296: F658-F665, 2009. First published December 3, 2008; doi:10.1152/ajprenal.90221.2008.
  51. Chang S, Hypolite JA, Mohanan S, Zderic SA, Wein AJ, Chacko S. (2009) Alteration of the PKC-mediated signaling pathway for smooth muscle contraction in obstruction-induced hypertrophy of the urinary bladder. Lab Invest. 89(7):823-32.
  52. Basha M, Labelle EF, Northington GM, Wang T, Wein AJ, Chacko S. (2009) Functional significance of muscarinic receptor expression within the proximal and distal rat vagina. Am J Physiol Regul Integr Comp Physiol. 297(5):R1486-93.
  53. Polyak E, Boopathi E, Mohanan S, Deng M, Zderic SA, Chacko S. (2009) Alteration of the caveolin expression and ultrastructure in bladder smooth muscle hypertrophy. J Urol. 182(5):2497-503.
  54. Daneshgari F, Liu G, Birder L, Hanna-Mitchell AT, Chacko S. (2009). Diabetic bladder dysfunction: current translational knowledge. J Urol. 182(6 Suppl):S18-26. Review.
  55. Chang S, Gomes CM, Hypolite JA, Marx J, Alanzi J, Zderic SA, Malkowicz B, Wein AJ, Chacko S. (2010). Detrusor overactivity is associated with the down-regulation of large conductance calcium- and voltage-activated potassium channel protein. Am J Physiol Renal Physiol. 298(6):F1416-23.
  56. Pan XQ, Gonzalez JA, Chang S, Chacko S, Wein AJ, Malykhina AP. (2010). Experimental colitis triggers the release of substance P and calcitonin gene-related peptide in the urinary bladder via TRPV1 signaling pathways. Exp Neurol. PMID: 20501335.
  57. Boopathi E, Gomes CM, Goldfarb R, John M, Srinivasan VG, Alanzi J, Malkowicz SB, Kathuria H, Zderic SA, Wein AJ, Chacko S. (2011) Transcriptional repression of caveolin-1 gene expression by GATA-6 in bladder smooth muscle hypertrophy in mice and humans. Am J Pathol 178(5):2236-51. PMID: 21514437.
  58. Zderic SA, Chacko S. (2011) Alterations in the contractile phenotype of the bladder; lessons for understanding physiological and pathological remodeling of smooth muscle. J Cell Mol Med. 16(2):203-17. PMID: 21707917.
  59. Chang AY, Sliwoski J, Butler S, Hearn G, Lassmann J, Chacko S, Canning DA, Zderic SA. (2012) Calcineurin mediates bladder wall remodeling secondary to partial outlet obstruction. Am J Physiol Renal Physiol. 2011 Oct;301(4):F813-22. PMID: 21775483.
  60. Zheng Y, Chang S, Boopathi E, Burkett S, John M, Malkowicz SB, Chacko S. (2012) Generation of a human urinary bladder smooth muscle cell line. In Vitro Cell Dev Biol Anim. 48(2):84-96.PMID: 22259013.
  61. Wang T, Kendig DM, Chang S, Trappanese DM, Chacko S, Moreland RS. (2012) Bladder Smooth Muscle Organ Culture Preparation Maintains the Contractile Phenotype. Am J Physiol Renal Physiol. 303(9):F1382-97. PMID: 22896042.
  62. Hypolite JA, Lei Q, Chang S, Zderic SA, Butler S, Wein AJ, Malykhina AP, Chacko S. (2013) Spontaneous and evoked contractions are regulated by PKC-mediated signaling in detrusor smooth muscle: involvement of BK channels. 304(5):F451-62. PMID: 23269650.
  63. Boopathi E, Hypolite JA, Zderic SA, Gomes CM, Malkowicz B, Liou HC, Wein AJ, Chacko S. (2013) GATA-6 and NF-κB Activate CPI-17 Gene Transcription and Regulate Ca2+ Sensitization of Smooth Muscle Contraction. Mol Cell Biol. 33(5):1085-102. PMID: 23275439.
 
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